Modern Pulmonary Arterial Hypertension Treatment Pathways and Combination Therapies

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• Evolution of PAH Treatment
• Three Main Therapeutic Pathways
• New Treatment Targets
• Assessing Disease Severity
• Combination Therapy Standard
• Treatment Progression Strategy
• Full Transcript

Evolution of PAH Treatment

Dr. Aaron Waxman, MD, describes a significant evolution in pulmonary arterial hypertension therapy. He recalls that treatment options were extremely limited decades ago. Initially, only calcium channel blockers and intravenous epoprostenol (Flolan) were available. Dr. Aaron Waxman, MD, notes that calcium channel blockers are ineffective for most PAH patients. The early prostacyclin therapy, while impactful, was very complex. It required continuous intravenous infusion via external pumps and Hickman catheters.

Three Main Therapeutic Pathways

Modern pulmonary arterial hypertension treatment focuses on three primary biological pathways. Dr. Aaron Waxman, MD, explains these are the endothelin pathway, nitric oxide pathway, and prostacyclin pathway. Pharmaceutical development over the past 20 years has produced several medications targeting these systems. These PAH treatments are now available as intravenous injections, oral medications, and even inhaled formulations. Dr. Aaron Waxman, MD, emphasizes that while these drugs are effective, they do not cure pulmonary arterial hypertension. They have tremendously improved patient survival, functional status, and quality of life.

New Treatment Targets

The future of pulmonary arterial hypertension treatment lies in novel therapeutic targets. Dr. Aaron Waxman, MD, highlights a growing focus on metabolic modulators. These new medications aim to change mitochondrial function in patients. There is also significant research into antiproliferative medication candidates. Dr. Waxman points out that some chemotherapeutic drugs are being repurposed from cancer treatment for PAH. Anti-inflammatory targets represent another promising avenue. This shift in approach means treating pulmonary arterial hypertension more like a metabolic neoplastic disease rather than solely a vasoconstrictor disorder.

Assessing Disease Severity

Determining the appropriate treatment strategy begins with a thorough assessment of disease severity. Dr. Aaron Waxman, MD, explains that physicians grade PAH severity similarly to heart failure. The World Health Organization (WHO) functional class system is the standard tool used for this evaluation. This classification helps doctors understand how limited a patient is in their physical abilities. It assesses symptoms like shortness of breath and signs of heart failure. This grading directly informs the selection of initial therapy and subsequent treatment decisions.

Combination Therapy Standard

Combination therapy has become the standard of care for pulmonary arterial hypertension. Dr. Aaron Waxman, MD, states this has been the established approach for the past two to three years. Clinical trial data now clearly demonstrates the benefit of using multiple medications together. This strategy mirrors the treatment of other complex diseases. Dr. Waxman acknowledges that PAH medications are expensive, which previously caused reluctance. However, the proven improvement in patient outcomes now justifies this comprehensive approach to therapy.

Treatment Progression Strategy

The progression of treatment for a patient with pulmonary arterial hypertension is tailored to their condition. Dr. Aaron Waxman, MD, outlines a common strategy during his discussion with Dr. Anton Titov, MD. Physicians often start with oral therapy for less severe cases. A typical initial combination includes a phosphodiesterase 5 inhibitor and an endothelin receptor antagonist. As patients progress or if they present with more severe disease, physicians consider adding prostacyclins. Dr. Waxman believes that using prostacyclins earlier in the disease course could yield even better results. This evolving, multi-targeted approach leads to more precise therapy and better patient outcomes.

Full Transcript

Leading pulmonary hypertension expert reviews PAH therapy and trends. How to select best treatment for pulmonary hypertension? What is new in treatment of pulmonary arterial hypertension?

Dr. Anton Titov, MD: Treatment of pulmonary arterial hypertension has come a long way since I got involved.

Dr. Aaron Waxman, MD: I first got involved in therapy of pulmonary arterial hypertension a long time ago. Then there was only one medication, or two medications. There were calcium channel blockers, which are ineffective for the vast majority of patients with pulmonary arterial hypertension.

There was epoprostenol, which was called Flolan at the time. It is an intravenous therapy. Prostacyclin was the other medication.

Prostacyclin had a big impact on patients, but it was a very complicated therapy. It involved intravenous continuous infusion. Injection had to be via external pumps and Hickman catheters.

Over the past 20 years, the focus in pulmonary arterial hypertension treatment has been on three main pathways: endothelin pathway, nitric oxide pathway, and prostacyclin pathway.

There are several medications developed for pulmonary arterial hypertension. They are intravenous injections and oral medications. There is even inhaled medication.

But none of the medications can cure pulmonary arterial hypertension. New medications are all effective in pulmonary arterial hypertension to a certain extent.

They have had a tremendous impact on survival and functional status of patients with pulmonary arterial hypertension. New medications improved quality of life.

But there is still tremendous room for development of effective pulmonary arterial hypertension therapy. More and more, the focus is now on metabolic modulators.

These medications change mitochondrial function. There are antiproliferative medication candidates. There are even chemotherapeutic medications being re-purposed from cancer treatment.

Also, there are anti-inflammatory targets in pulmonary arterial hypertension. It is a complicated method of therapy.

We are moving much more into the realm of successful therapy of pulmonary arterial hypertension. We are starting to treat pulmonary arterial hypertension like a metabolic neoplastic disease.

It is more than a vasoconstrictor disease. Most of the focus previously has been on vascular constriction aspects of pulmonary arterial hypertension.

Dr. Anton Titov, MD: There is a patient who has been diagnosed with pulmonary arterial hypertension. Let’s suppose that the diagnosis has been established. Are there particular stages of therapy of pulmonary arterial hypertension?

Are there lines of therapy in pulmonary arterial hypertension, similarly to the cancer treatment?

What is a typical progression of treatment for a patient with pulmonary arterial hypertension?

Dr. Aaron Waxman, MD: We grade a severity of disease in a patient with pulmonary arterial hypertension. We determine a severity grade scale much like we do in heart failure. We use the WHO functional class approach.

Over the past two to three years, it has become the standard of care for pulmonary arterial hypertension to use a combination therapy. We would use a combination treatment for most other complicated diseases.

These medications for pulmonary arterial hypertension tend to be quite expensive. There has been a reluctance over the past years to treat pulmonary arterial hypertension purely because of expense.

Now we have clinical trial data that show a clear benefit in pulmonary arterial hypertension treatment. It is best to use a combination therapy with several medications.

It depends on how sick a patient with pulmonary arterial hypertension might be. By how sick, I mean how short of breath the patient is. How limited is a patient in physical ability?

Dr. Anton Titov, MD: Are they having problems with heart failure?

Dr. Aaron Waxman, MD: We might start with just oral therapy for pulmonary arterial hypertension. Then we can use a combination of two medications.

Usually, our treatment is a phosphodiesterase 5 inhibitor in combination with an endothelin antagonist. Patients with pulmonary arterial hypertension progress in severity.

Then we start to think more and more about prostacyclins. But the truth is that prostacyclins are still our best therapies for pulmonary arterial hypertension.

Probably if we use them earlier in disease, we'd get even better results. It is a moving target how we treat patients with pulmonary arterial hypertension.

But it is good. It is becoming a more complex targeting of pulmonary arterial hypertension disease. We use a more precise therapeutic approach to pulmonary arterial hypertension.

That leads to better outcomes for patients.